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FINDING CURES TOGETHER<sup>SM</sup>

Many Childhood Cancer Survivors Carry Mutations in Cancer Predisposition Genes, Raising Risk of Later Disease

4/3/2017

WASHINGTON — Whole-genome sequencing conducted on a large cohort of childhood cancer survivors indicated that many survivors harbor mutations in cancer predisposition genes, significantly increasing their risk of developing a subsequent neoplasm (SN) later in life, according to data presented here at the AACR Annual Meeting 2017, April 1-5.

“The remarkable advances realized over the past four decades in the treatment and survival of pediatric cancer patients is one of the most notable success stories within the cancer field,” said the study’s co-senior author, Les Robison, PhD, chair of the Department of Epidemiology and Cancer Control at St. Jude Children’s Research Hospital in Memphis, Tennessee. “However, childhood cancer survivors are at increased risk of subsequent neoplasms, largely considered to be therapy-related.” Les Robison, PhD

Today, Robison explained, many forms of childhood cancer have cure rates of more than 80 percent. As a result, there are now more than 400,000 long-term survivors of childhood cancer in the United States.

In order to explore the role of genetics in these survivors’ increased risk of SNs, the research team led by Dr. Jinghui Zhang, chair of the Department of Computational Biology at St. Jude, analyzed the results of whole genome and exome sequencing that were performed on 3,007 participants of the St. Jude Lifetime Cohort who had survived childhood cancer for five years or longer. Survivors underwent a comprehensive clinical assessment, treatment exposures were extracted from medical records, and SNs were pathologically or radiologically confirmed.

The researchers identified 1,117 SNs in 434 survivors. Of these survivors, 93 had been diagnosed with two or more histologically distinct SNs. Overall, 25.5 percent of the survivors developed a SN by age 45, most commonly non-melanoma skin cancer, meningioma, thyroid, and breast cancer.

The results showed that 12 percent of the survivors had a pathogenic or likely pathogenic mutation in one of 156 genes associated with an increased risk of cancer. The most common mutations were in the genes of RB1, NF1, BRCA2, BRCA1, and TP53.

Among the survivors who had never received radiotherapy, those who carried a pathogenic or likely pathogenic mutation were six times more likely to develop an SN than those who did not carry such mutations. The chance of developing two or more SNs increased 24-fold for the survivors carrying mutations.

Among the survivors who were exposed to radiotherapy, those who carried a pathogenic or likely pathogenic mutation had a two-fold increased risk for developing two or more SNs compared with those who did not carry a mutation.

Robison emphasized that various factors contribute to the increased risk and to the types of SNs experienced by childhood cancer survivors. For example, he said, radiation exposure increases the risk of subsequent neoplasms such as meningioma, non-melanoma skin cancer, breast cancer, thyroid cancer, and sarcomas. The study results now demonstrate that genetics independently add to the risk for breast cancer, thyroid cancer, and sarcomas, he added.

“Our findings have immediate implications for the growing population of long-term survivors of childhood cancer,” Robison said. First of all, he said, “We are recommending that survivors of childhood cancer who develop specific types of subsequent neoplasms receive genetic counseling. 

“In addition, we believe that these findings will contribute to future decisions relating to recommendations for personalized therapeutic approaches based on genetic profiles for children who are newly diagnosed with cancer,” Robison said.

Zhaoming Wang, PhD, co-lead author, said that future research will be necessary to continue to follow the St. Jude survivors, to replicate this study’s findings in other populations of childhood cancer survivors, and to understand possible links between genetic factors and cancer treatment exposures. For survivors, this research could help guide their decisions on family planning and on cancer prevention strategies, such as regular screening. Zhaoming Wang, PhD

Robison said a limitation of the study is that it was based on the ability to follow up with survivors. Some former patients may have died, either from a subsequent neoplasm or another chronic health condition related to their cancer therapy. Therefore, he said, the study estimates should be considered a conservative estimate of the prevalence of mutations.

Wang and Carmen Wilson, PhD, of the Department of Epidemiology and Cancer Control at St. Jude, were the co-lead authors of this study. Zhang and Robison were co-senior authors.

This study was funded by the American Lebanese Syrian Associated Charities (ALSAC) and by the National Cancer Institute. The authors declare no conflicts of interest.

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